Tropomyosin 1 genetically constrains in vitro hematopoiesis

Abstract

Identifying causal variants and genes from human genetics studies of hematopoietic traits are important to enumerate basic regulatory mechanisms underlying these traits, and could ultimately augment translational efforts to generate platelets and/or red blood cells in vitro. To identify putative causal genes from these data, we performed computational modelling using available genome-wide association data sets for platelet traits. Our model identified a joint collection of genomic features enriched at established platelet trait associations and plausible candidate variants. Additional studies associating variation at these loci with change in gene expression highlighted the Tropomyosin 1 (TPM1) among our top-ranked candidate genes. CRISPR/Cas9-mediated TPM1 knockout in human induced pluripotent stem cells (iPSCs) enhanced hematopoietic progenitor development, increasing total megakaryocyte as well as erythroid cell yields. Our findings may help explain human genetics associations and identify a novel genetic strategy to enhance in vitro hematopoiesis.

From development toward therapeutics, a collaborative effort on blood progenitors

“…With interest in improving strategies to expand megakaryocyte and platelet production in vitro, he followed a human genetic approach to identify polymorphisms in TPM1 that lead to altered platelet traits. Using a primitive hematopoiesis system, wherein human iPSCs could be differentiated into primitive streak to the mesoderm stage, he interrogated the effect of loss of TPM1 compared with wild-type cultures (Thom et al, 2019(Thom et al, , 2020. The mesodermal cells normally acquire an endothelial fate, and the hemogenic population within this endothelium specifically undergo EMT to produce HPCs.…”

Mechanistic and Translational Advances Using iPSC-Derived Blood Cells

“…The refinement of iPSC systems to produce definitive-like hematopoiesis models [20,21] and increase in vitro cell production [8,62], will be essential for improving mechanistic studies, small molecule screening, and gene editing approaches. These models may also better support translational research goals in blood bank screening and cellular therapeutics [22].…”

Mechanistic and Translational Advances Using iPSC-Derived Blood Cells

“…This commentary has used selected vignettes to show how human iPSC model systems can be used to study mechanisms by which blood cells contribute to hematopoietic and nonhematopoietic disorders, and guide platform development for therapeutic approaches. The refinement of iPSC systems to produce definitive-like hematopoiesis models [23,24] and increase in vitro cell production [8,65], will be essential for improving mechanistic studies, small molecule screening, and gene editing approaches. These models may also better support translational research goals in blood bank screening and cellular therapeutics [25].…”

“…Hematopoiesis is one of the best characterized developmental systems, given relatively accessible patient samples, and excellent cell and animal models [2,3]. Population studies have identified thousands of genomic loci that affect human blood traits [4], leading to translationally relevant developmental insights (e.g., [5][6][7][8][9][10]). Mechanistic studies using cells derived from clinically affected patients also offer increasingly powerful approaches to discover genetic factors that regulate hematopoiesis, and to identify novel treatment strategies.…”